Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
Semin Cell Dev Biol. 2012 Jun;23(4):429-36. doi: 10.1016/j.semcdb.2012.01.011. Epub 2012 Jan 24.
Regulation of Notch signaling is critical to development and maintenance of most eukaryotic organisms. The Notch receptors and ligands are integral membrane proteins and direct cell-cell interactions are needed to activate signaling. Ligand-expressing cells activate Notch signaling through an unusual mechanism involving Notch proteolysis to release the intracellular domain from the membrane, allowing the Notch receptor to function directly as the downstream signal transducer. In the absence of ligand, the Notch receptor is maintained in an autoinhibited, protease resistant state. Genetic studies suggest that Notch ligands require ubiquitylation, epsin endocytic adaptors and dynamin-dependent endocytosis for signaling activity. Here we discuss potential models and supporting evidence to account for the absolute requirement for ligand endocytosis to activate signaling in Notch cells. Specifically, we focus on a role for ligand-mediated endocytic force to unfold Notch, override the autoinhibited state, and activate proteolysis to direct Notch-specific cellular responses.
Notch 信号通路的调控对于大多数真核生物的发育和维持至关重要。Notch 受体和配体是完整的膜蛋白，需要直接的细胞间相互作用来激活信号通路。配体表达细胞通过一种不寻常的机制激活 Notch 信号通路，涉及 Notch 蛋白水解，将细胞内结构域从膜上释放出来，使 Notch 受体能够直接作为下游信号转导器发挥作用。在没有配体的情况下， Notch 受体保持在自动抑制、蛋白酶抗性状态。遗传研究表明， Notch 配体需要泛素化、衔接蛋白 epsin 和依赖于 dynamin 的内吞作用才能发挥信号活性。在这里，我们讨论了潜在的模型和支持性证据，以解释 Notch 细胞中配体内吞激活信号的绝对要求。具体来说，我们专注于配体介导的内吞力在解开 Notch、克服自动抑制状态以及激活蛋白水解以指导 Notch 特异性细胞反应中的作用。
